Aspergillus species have emerged as an important cause of life-threatening infections in immunocompromised patients. This expanding population is composed of patients with prolonged neutropenia, advanced HIV infection, and inherited immunodeficiency and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) and/or lung transplantation. This document constitutes the guidelines of the Infectious Diseases Society of America for treatment of aspergillosis and replaces the practice guidelines for Aspergillus published in 2000 . The objective of these guidelines is to summarize the current evidence for treatment of different forms of aspergillosis. The quality of evidence for treatment is scored according to a standard system used in other Infectious Diseases Society of America guidelines. This document reviews guidelines for management of the 3 major forms of aspergillosis: invasive aspergillosis, chronic (and saprophytic) forms of aspergillosis, and allergic forms of aspergillosis. Given the public health importance of invasive aspergillosis, emphasis is placed on the diagnosis, treatment, and prevention of the different forms of invasive aspergillosis, including invasive pulmonary aspergillosis, sinus aspergillosis, disseminated aspergillosis, and several types of single-organ invasive aspergillosis. There are few randomized trials on the treatment of invasive aspergillosis. The largest randomized controlled trial demonstrates that voriconazole is superior to deoxycholate amphotericin B (D-AMB) as primary treatment for invasive aspergillosis. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients (A-I). Although invasive pulmonary aspergillosis accounts for the preponderance of cases treated with voriconazole, voriconazole has been used in enough cases of extrapulmonary and disseminated infection to allow one to infer that voriconazole is effective in these cases. A randomized trial comparing 2 doses of liposomal amphotericin B (L-AMB) showed similar efficacy in both arms, suggesting that liposomal therapy could be considered as alternative primary therapy in some patients (A-I). For salvage therapy, agents include lipid formulations of amphotericin (LFAB; A-II), posaconazole (B-II), itraconazole (B-II), caspofungin (B-II), or micafungin (B-II). Salvage therapy for invasive aspergillosis poses important challenges with significant gaps in knowledge. In patients whose aspergillosis is refractory to voriconazole, a paucity of data exist to guide management. Therapeutic options include a change of class using an amphotericin B (AMB) formulation or an echinocandin, such as caspofungin (B-II); further use of azoles should take into account host factors and pharmacokinetic considerations. Refractory infection may respond to a change to another drug class (B-II) or to a combination of agents (B-II). The role of combination therapy in the treatment of invasive aspergillosis as primary or salvage therapy is uncertain and warrants a prospective, controlled clinical trial. Assessment of patients with refractory aspergillosis may be difficult. In evaluating such patients, the diagnosis of invasive aspergillosis should be established if it was previously uncertain and should be confirmed if it was previously known. The drug dosage should be considered. Management options include a change to intravenous (IV) therapy, therapeutic monitoring of drug levels, change of drug class, and/or combination therapy. Antifungal prophylaxis with posaconazole can be recommended in the subgroup of HSCT recipients with graft-versus-host disease (GVHD) who are at high risk for invasive aspergillosis and in neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome who are at high risk for invasive aspergillosis (A-I). Management of breakthrough invasive aspergillosis in the context of mould-active azole prophylaxis is not defined by clinical trial data. The approach to such patients should be individualized on the basis of clinical criteria, including host immunosuppression, underlying disease, and site of infection, as well as consideration of antifungal dosing, therapeutic monitoring of drug levels, a switch to IV therapy, and/or a switch to another drug class (B-III). Certain conditions of invasive aspergillosis warrant consideration for surgical resection of the infected focus. These include but are not limited to pulmonary lesions contiguous with the heart or great vessels, invasion of the chest wall, osteomyelitis, pericardial infection, and endocarditis (B-III). Restoration of impaired host defenses is critical for improved outcome of invasive aspergillosis (A-III). Recovery from neutropenia in a persistently neutropenic host or reduction of corticosteroids in a patient receiving high-dose glucocorticosteroids is paramount for improved outcome in invasive aspergillosis. A special consideration is made concerning recommendations for therapy of aspergillosis in uncommon sites, such as osteomyelitis and endocarditis. There are very limited data on these infections, and most involve D-AMB as primary therapy simply because of its long-standing availability. Based on the strength of the randomized study, the panel recommends voriconazole for primary treatment of these very uncommon manifestations of invasive aspergillosis (B-III). Management of the chronic or saprophytic forms of aspergillosis varies depending on the condition. Single pulmonary aspergillomas may be best managed by surgical resection (B-III), whereas chronic cavitary and chronic necrotizing pulmonary aspergillosis require long-term medical therapy (B-III). The management of allergic forms of aspergillosis involves a combination of medical and anti-inflammatory therapy. For example, management of allergic bronchopulmonary aspergillosis (ABPA) involves the administration of itraconazole and corticosteroids (A-I).
Bibliographical noteFunding Information:
Potential conflicts of interest. T.J.W. has Cooperative Research & Development Agreements with Vicuron (subsequently acquired by Pfizer) and with Fujisawa (Astellas). T.F.P. has had grant support from Astellas Pharma US, Enzon, Nektar Therapeutics, Merck, Pfizer, and Schering-Plough; has been a consultant for Merck, Pfizer, Schering-Plough, Basilea, Nektar Therapeutics, and Stiefel Laboratories; and has been on the speaker’s bureau for Merck, Pfizer, and Schering-Plough. E.J.A. has received grant support from Astellas, Curagen, Enzon, Nuvelo, OrthoBiotech, and Pfizer; has been a consultant for Astellas, Gilead Sciences, Merck, Pfizer, and Schering Plough; and has been on the speaker’s bureau for Astellas, Gilead Sciences, Merck, and Pfizer. D.W.D. has received grant support from Astellas, Merck, Pfizer, F2G, OrthoBiotech, Sigma-Tau, Indevus, Basilea, Fungal Research Trust, Wellcome Trust, and Moulton Trust; has been an advisor/consultant for Merck, Basilea, Vicuron (now Pfizer), Schering-Plough, Indevus, F2G, Nektar, Daiichi, Sigma Tau, Astellas, and York Pharma; has been paid for speaking on behalf of Astellas, Merck, GSK, Chiron, AstraZenca, and Pfizer; and holds founder shares in F2G and Myconostica. R.H. has been a member of the advisory board for Astellas, Gilead, Merck, Pfizer, and Schering-Plough and has been a member of the speaker’s bureau of Gilead, Pfizer, Schering-Plough, and Zeneus. D.P.K. has received research support and honoraria from Schering-Plough, Pfizer, Astellas Pharma, Enzon Pharmaceuticals, and Merck. K.A.M. has served as a consultant for Astellas, Enzon, Basilea, Merck, Nektar Therapeutics, Pfizer, Schering-Plough, Bas-ilea, Merck, and Nektar. V.A.M. is a consultant for Schering-Plough, Berlex, and BiogenIDEC and is on the speaker’s bureau for Amgen, Berlex, Celgene, Merck, Pfizer, and Schering-Plough. B.H.S. has received speaker honoraria from Merck and Pfizer; has served as a consultant/advisor for Pfizer, Sch-ering-Plough, Berlex, and Enzon; has been a compensated member of a data review committee for Schering-Plough; and has received laboratory support from Enzon and Pfizer. W.J.S. has served on the speaker’s bureau for Pfizer and Astellas and has served as a consultant for Astellas, Merck, and Enzon. D.A.S. has served on the advisory boards for Merck, Schering-Plough, and Gilead; has served as a speaker for Janssen, Enzon, and Astellas; and has received grant support from Merck, Pfizer, Gilead, Schering-Plough, Enzon, and Astellas. J.-A.v.B. has served on the speaker’s bureau for Schering-Plough and Astellas; has served as a clinical trial investigator for Schering-Plough, Merck, and Astellas; and has served as a consultant for Merck. J.R.W. has received speaker’s honoraria from Pfizer and Merck, has received grants from Merck and Pfizer, and has served as an advisor for Pfizer, Merck, and Schering-Plough.